1-And/or 7-substituted-6-hydroxy (or oxo)-3-decahydroquinoline carboxylic acids

ABSTRACT

Octahydropyrazolo[3,4-g]quinolines, dopamine agonists, useful in treatment of Parkinsonism and in inhibiting secretion of prolactin.

This is a division of application Ser. No. 031,641 filed Apr. 19, 1979,which is a continuation-in-part of our their copending application Ser.No. 005,061 filed Jan. 22, 1979, now abandoned.

DESCRIPTION OF THE INVENTION

This invention provides octahydropyrazolo[3,4-g]quinolines of theformula: ##STR1## wherein R is H, CN, (C₁ -C₃) alkyl, allyl or benzyl;R¹ is H, COOZ' or CH₂ X wherein Z' is H, (C₁ -C₂)-alkyl orphenyl-substituted (C₁ -C₂)alkyl and X is Cl, I, Br, OH, OCH₃, SCH₃, CN,OSO₂ (C₁ -C₃)alkyl, OSO₂ phenyl, OSO₂ tolyl, SO₂ CH₃ or CO-NH₂ ;

and R² is SO₂ (C₁ -C₃)alkyl, SO₂ phenyl, SO₂ tolyl, or H;

and pharmaceutically-acceptable acid addition salts thereof.

Compounds according to the above formulas in which R is C₁ -C₃ alkyl orallyl and R¹ is H or CH₂ X where X is CN, SCH₃, SO₂ CH₃, OCH₃ or CONH₂and their pharmaceutically acceptable acid addition salts are usefulchiefly as dopamine agonists, while those compounds in which R is H, CN,C₁ -C₃ alkyl, allyl or benzyl and R¹ is COOZ' or CH₂ X wherein Z' is H,(C₁ -C₂)alkyl or phenyl-substituted (C₁ -C₂)-alkyl and X is Cl, Br, I,OH, OSO₂ (C₁ -C₃)alkyl, O-SO₂ phenyl or O-SO₂ tolyl, although not devoidof dopamine agonist activity, are chiefly useful as intermediates forthe preparation of the above mentioned more active agonists. All saltsof these intermediates are useful in purification or syntheticprocedures.

In the above formulas, the term "(C₁ -C₂)-alkyl" includes methyl andethyl and "(C₁ -C₃)-alkyl" includes also n-propyl and isopropyl. Theterm "tolyl" includes p, m and o-tolyl.

The pharmaceutically-acceptable acid addition salts of this inventioninclude salts derived from inorganic acids such as: hydrochloric acid,nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodicacid, nitrous acid, phosphorous acid and the like, as well as saltsderived from nontoxic organic acids such as aliphatic mono anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicand alkandioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such pharmaceutically-acceptable salts thus include sulfate,pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, butyne-I,4-dioate,hexyne-11,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, malate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts.

Compounds according to Ia above are named systematically as4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolines and thoseaccording to Ib as4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolines. These twostructures represent a tautomeric pair when R² is H and the tautomersrepresented by the structures are in dynamic equilibrium. In addition,compounds represented by Formulas Ia and Ib above when R¹ is H have twochiral centers, the ring junction carbons at 8a and 4a. Thus, thecompounds can occur as two racemates, ordinarily denominated as thetrans-dl racemate and the cis-dl racemate. It is believed, however,according to the best evidence from ¹³ C NMR spectral data, that thecyanoborohydride reduction process which introduces hydrogens at thequinoline bridgehead, a step in the synthetic procedure used to preparethe compounds of this invention, yields a trans-fuseddecahydroquinoline. While the arguments for the trans configurationbased upon ¹³ C NMR spectral data are compelling, an X-raycrystallographic investigation has also been carried out on a nicelycrystalline enaminoketone in the decahydroquinoline series (VIII,R=CH₃). This x-ray analysis indicates clearly that the ring junction inthe quinoline moiety is trans. Further operations on thedecahydroquinoline molecule to condense a pyrazole ring thereon do notalter the configuration of the bridge-head hydrogens. Thus, only thetrans racemate is prepared by the synthetic procedures to be disclosedhereinafter and the compounds of this invention are preferablyrepresented as the trans-dl stereoisomers. The two trans stereoisomersof the 2H tautomer (R² =H) can be represented as follows: ##STR2## IIaand IIb represent a racemic pair. A similar racemic pair can be drawnfor the 1H tautomer. ##STR3## IIc and IId also represent a racemic pair.

Resolution of these racemates into their optical antipodes can beaccomplished by procedures known to those skilled in the art, and theindividual trans-d and trans-l isomers are included within the scope ofthis invention.

In addition, when R¹ is other than H, a third chiral center isintroduced at C-7. However, it is presently believed that theconfiguration of the C-7 group is chiefly beta relative to an alpha 8ahydrogen as in IIa. In the mirror image, IIb, R¹ is alpha with respectto 8a being beta. Thus, the trans-dl 7-substitutedoctahydropyrazolo[3,4-g]quinolines of this invention are providedsubstantially as a single racemate or diastereoisomeric pair.

The following compounds illustrate the scope of our invention.

trans-dl-5-methyl-7-methoxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline,

trans-d-5-benzyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolinehydrochloride,

trans-l-5-allyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinemaleate,

trans-dl-5-ethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline,

trans-dl-5-n-propyl-7-methylsulfonylmethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo-[3,4-g]quinolinetartrate,

trans-d-5-methyl-7-cyanomethyl-4,4a-5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline,

trans-dl-5-benzyl-7-carboxy-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinemesylate,

trans-dl-1-methanesulfonyl-5-methyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolinemesylate,

trans-dl-5-ethyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolinesulfate,

trans-dl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinesulfate,

trans-dl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolinesulfate,

trans-dl-2-p-tosyl-5-methyl-7-p-tosyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinesulfate,

trans-dl-7-hydroxymethyl-4,4a,5,6,7,-8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinehydrochloride,

trans-dl-5-ethyl-7-chloromethyl-4,4a,-5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolinetartrate,

trans-dl-5-n-propyl-7-carboamidomethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinefumarate,

trans-dl-5-isopropyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline,

trans-dl-5-benzyl-7-methoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline,

trans-dl-7-methylmercaptomethyl-4,4a,-5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline,

trans-dl-5-n-propyl-7-methoxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinemaleate,

trans-dl-5-ethyl-7-cyanomethyl-4,4a,-5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline,

trans-dl-5-allyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline,

trans-dl-5-allyl-7-(α-phenylethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinoline,

trans-dl-5-ethyl-7-hydroxymethyl-4,4a,-5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline.

For compounds listed above in which neither N-1 nor N-2 is substituted(R² =H), it should be understood that each name also comprehends theother tautomer since an equilibrium mixture of the two tautomers isalways present. The 2H tautomer apparently predominates in several ofthe tautomeric mixtures. In addition, the orientation of substituents isnot given, nor is the configuration of the hydrogens at 4a and 8a, butit is understood that the hydrogens are trans to one another and thatthe 7 substituent is "trans" to the 8a hydrogen; i.e., when the 8ahydrogen is alpha, the 7 substituent is beta and when the 8a hydrogen isbeta, the 7 substituent is oriented in the alpha configuration.

The compounds of this invention in which R¹ and R² are H are preparedaccording to the following procedure as outlined in Reaction Scheme I.In the Reaction Scheme, only one stereoisomer of the racemic pair, the4aβ, 8aα isomer, has been drawn for convenience but it should beremembered that each decahydroquinoline and eachoctahydropyrazolo[3,4-g]quinoline exists as a racemate. ##STR4## In theabove reaction scheme, Z-CO is an acyl protecting group in which Z is(C₁ -C₃)alkyl, (C₂ -C₃)alkenyl, (C₂ -C₃)alkynyl, (C₅ -C₆)cycloalkyl,phenyl or substituted phenyl wherein the substituting group can bemethyl, methoxy, chloro and the like at any position of the phenyl ring.Illustratively, Z-CO can be acetyl, propionyl, butyryl, propiolyl,acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl, m-methoxybenzoyl etc.

Z'' is defined hereinbelow in the discussion of Reaction Scheme II. Inaccordance with Reaction Scheme I, 4-acyloxycyclohexanone prepared bythe procedure of E. R. H. Jones and F. Sondheimer, J. Chem. Soc., 615,(1949) for 4-benzoyloxycyclohexanone, is reacted with pyrrolidine in thepresence of an acid catalyst to yield the pyrrolidine enamine. Thisenamine is in turn reacted with acrylamide to produce a mixture ofdl-6-acyloxy-3,4,5,6,7,8-hexahydro-2(1H)quinolinone anddl-6-acyloxy-3,4,4a,5,6,7-hexahydro-2(1H)quinolinone represented byformula III, the dotted lines indicating the alternative positions ofthe double bond.

Next, the acidic nitrogen (acidic since it is alpha to a carbonyl group)is alkylated with an alkyl halide RX wherein R has the same meaning ashereinabove and X is a halogen such as Cl, Br or I, in the presence ofsodium hydride to yield a mixture of dl-1-(C₁ -C₃) alkyl (or allyl orbenzyl)-6-acyloxy-3,4,5,6,7,8-hexahydro-2(1H) quinolinone and its Δ⁸isomer (IV). Reduction of this amide with lithium aluminum hydride orother suitable organometallic reducing agent yields a mixture ofdl-1-(C₁ -C₃) alkyl (or allyl orbenzyl)-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and its Δ⁸ isomer.In this reaction mixture, conditions are encountered which also serve tohydrogenolyze the acyloxy group to a hydroxyl group at C-6. Thisdl-1-(C₁ -C₃) alkyl (or allyl or benzyl)-6-hydroxyoctahydroquinoline isnext converted to an ammonium salt by treatment with hydrochloric acid,and the ammonium salt is then reduced with sodium cyanoborohydride toyield trans-dl-1-(C₁ -C₃) alkyl (or allyl orbenzyl)-6-hydroxydecahydroquinoline (VI). Next, the trans-dl-1-(C₁ -C₃alkyl, allyl, or benzyl)-6-hydroxydecahydroquinoline (VI) is oxidizedusing, preferably, chromium trioxide in acetic acid, to yield thecorresponding 6-oxo compound (VII). This 6-oxo compound (VII) is reactedwith dimethylformamide dimethylacetal to yield a7-dimethylaminomethylene-6-oxo-derivative (VIII). Reaction of thisderivative with hydrazine hydrate yields a tautomeric mixture of atricyclic derivative, predominately trans-dl-5-[(C₁ -C₃)alkyl, allyl orbenzyl)]-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo-[3,4-g]quinoline (IX)and its 1H tautomer (IXa) in smaller amount.

The compounds of this invention wherein R is C₁ -C₃ alkyl or allyl, thedopamine agonists, can also be prepared from compounds in which R isbenzyl. In this procedure, the benzyl group is removed by reductivecleavage or by treatment with cyanogen bromide to yield, eventually, acompound according to IX or IXa in which R is H progressing thru anintermediate when cyanogen bromide is used in which R is CN. Thisdebenzylated compound can then be alkylated with a lower alkyl halide,or alternatively it may be reductively alkylated using acetaldehyde,acrolein or propionaldehyde in each instance with sodiumcyanoborohydride to yield the desired N-alkyl or allyl derivative. Theusual conditions for removing an N-benzyl group are hydrogen with apalladium-on-carbon catalyst or reaction with cyanogenbromide followedby reductive (Zn and acetic acid) cleavage of the N-cyano compound.

In the above reaction scheme, it is apparent from an inspection of thedl-trans-1(substituted)-6-ketodecahydroquinoline (VII) that reactionwith dimethylformamide dimethylacetal could take place at either C-5 orC-7 since both these carbons are alpha to the ketone group and thusavailable for reaction. The same x-ray crystallographic analysis of theenamine (VIII) discussed above clearly indicated that reaction had takenplace at C-7 rather than C-5. Hence, the final tricyclic compounds, IXand IXa, are the linear pyrazolo[3,4-g]quinolines rather than theangular tricyclic compounds (which would be named as4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[2,3-i]quinolines.

The compounds of this invention in which R¹ is other than H but R²remains H are prepared according to a slightly different procedureillustrated generally in Reaction Scheme II. As in Reaction Scheme I theprocedure is exemplified with only (referring to the stereochemistry ofthe bridgehead) a single stereoisomer, the 4aβ, 8aα isomer. ##STR5##wherein Z and Z'' have the same significance as in Reaction Scheme I,Hal is chloro or bromo and Z' is part of a readily hydrolyzable groupZ'O-CO such as (C₁ -C₂)alkyl, phenyl substituted (C₁ -C₂)alkyl,illustratively benzyl, phenethyl, p-methoxybenzyl, methyl, ethyl etc.

In accordance with the Reaction Scheme II, a 4-acyloxycyclohexanone isreacted with an α-halomethylacrylate ester, for illustrative purposes,the ethyl ester and an amine, RNH₂, wherein R is C₁ -C₃ alkyl, allyl orbenzyl. The product of this reaction is a mixture ofdl-1-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,3,4,5,6,7,8-octahydroquinolineanddl-1-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,3,4,4a,5,6,7-octahydroquinolinerepresented by X in which the dotted line indicates the alternatepositions of the double bonds. The hydrochloride salts of these isomerswere prepared and the resulting mixture reduced with sodiumcyanoborohydride to yieldtrans-dl-1-substituted-3-ethoxycarbonyl-6-acyloxydecahydroquinoline(XI). Hydrolysis of this diester to yield a 6-hydroxy-3-carboxylic acidfollowed by reesterification of the carboxylic acid group with ethanolor other suitable alcohol in the presence of acid yieldstrans-dl-1-substituted-3-ethoxycarbonyl-6-hydroxydecahydroquinoline(XII). Oxidation of the hydroxy group with Sarett's Reagent (pyridinehydrochloride and chromium trioxide) produces the corresponding 6-oxocompound (XIII). Treatment of this 6-oxo derivative with adimethylformamide acetal, preferably dimethylformamide dimethylacetal,results in reaction at C-7 (adjacent to the keto group) to givetrans-dl-1-substituted-3-ethoxycarbonyl-6-oxo-7-(dimethylaminomethylene)-decahydroquinoline(XIV). Reaction of this derivative as in Reaction Scheme I above withhydrazine hydrate results in a mixture comprisingtrans-dl-5-substituted-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolineand its 2H tautomer (represented by XV as a single stereoisomer). Thecompound can be isolated and purified as the free base or as thedihydrochloride salt, prepared according to conventional procedures.

Acetals of dimethylformamide useful in producing compound VIII inReaction Scheme I and compound XIV in Reaction Scheme II have thegeneral formula (CH₃)₂ N--CH--(OZ'')₂ in which Z'' is (C₁ -C₈)-alkyl,(C₅ -C₆)cycloalkyl, (C₃ -C₄)alkenyl, (C₃ -C₄)-alkynyl and the like. Weprefer to employ one of the commercially available acetals ofdimethylformamide; i.e.; the dimethyl, diethyl, diisopropyl, dibutyl,dicyclohexyl, dipropyl or dineopentyl acetals.

In formula XV above, R is (C₁ -C₃)alkyl, allyl or benzyl. Theoctahydropyrazolo[3,4-g]quinoline of Formula XV represents a singletautomer, the 2H tautomer, and only one diastereoisomer. The mirrorimage of XV is also prepared and is included within the scope of thisinvention. We believe based upon analogy with the D-ergolines that thediastereoisomer XV is the isomer having dopamine agonist activity. Thetrans-dl racemate, which contains XV and its mirror image, is of courseuseful as a dopamine agonist, even though most of the desired activityresides in one of its component stereoisomers.

Intermediates described in Reaction Schemes I and II, having thefollowing structures, form a part of this invention ##STR6## wherein Ris (C₁ -C₃)alkyl, allyl or benzyl and

R¹ is COOZ' wherein Z' is (C₁ -C₂)alkyl or phenyl-substituted (C₁-C₂)alkyl. These intermediates are prepared by the methods set forth inthose reaction schemes, in the accompanying detailed description and inthe Examples which follow.

Compounds according to XV above in which R is ethyl, allyl or n-propylcan be prepared by two different procedures. First, the amine, RNH₂,used in preparing X can be ethyl, n-propyl or allyl thus introducing thegroup directly. Alternatively a compound according to XV in which R ismethyl or benzyl can be transformed into a compound in which R is H byremoving the methyl or benzyl group by reaction with cyanogen bromide.The intermediate 5-cyano (R is CN) derivative can be reductively cleaved(zinc plus acetic acid) to yield a compound in which R is H. Inaddition, the benzyl group can be removed by hydrogenation withpalladium-on-carbon to yield those intermediates in which R=H.Alkylation of the secondary amine can be accomplished by reaction withan alkyl halide--RCl, RBr or RI. Alternatively, the secondary aminegroup can be reacted with acetaldehyde, acrolein, or propionaldehydeunder reducing conditions (NaBH₃ CN) to yield an N-ethyl, N-allyl orN-n-propyl derivative.

The dopamine agonists of this invention, those compounds in which R¹ isCH₂ X wherein X is CN, OCH₃, SCH₃, SO₂ CH₃ or CO-NH₂, are prepared fromcompound XV according to Reaction Scheme III below ##STR7## wherein Y isa "leaving" group: Cl, Br, OSO₂ phenyl, O-tosyl or SO₂ (C₁ -C₃)alkyl, R²is H, SO₂ phenyl, tosyl or SO₂ (C₁ -C₃)alkyl, and X is CN, SCH₃, OCH₃ orSO₂ CH₃.

In Reaction Scheme III, as before, only one tautomer, the 2H tautomer,is illustrated. Furthermore, the 2H tautomer exists as a racemate andonly one diastereoisomer is illustrated, the 4aβ, 7β, 8aα isomer. Themirror image compound is, of course, also produced since it constituteshalf of the starting material, XV. The trans-dl racemates of XVIII areuseful as dopamine agonists because of their content of active agonist.The intermediate racemates, XV, XVI and XVII are useful in that eachcontains a diastereoisomer which can be chemically transformed to anactive dopamine agonist.

According to Reaction Scheme III, atrans-dl-5-substituted-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline-7-carboxylateester is reduced with a metal hydride reducing agent such as LiAlH₄ to apyrazolo[3,4-g]quinoline with a 7-hydroxymethyl group (XVI). Thethus-produced hydroxyl is next replaced with a "leaving group"; i.e., agroup readily displaced by a nucleophilic reagent, including chlorine,bromine and the halogen-like esters, tosylate (usually p-toluenesulfonate), alkyl sulfonate, benzene sulfonate etc. to produce acompound of structure XVII. The Cl or Br leaving groups are introducedby reaction with PCl₃, SOCl₂, PCl₅, POCl₃, PBr₃ and the like, and thesulfonate esters by reaction with the corresponding sulfonyl chloride.This latter reaction results also in reaction on the pyrazole nitrogento produce the compounds of this invention in which R² is (C₁ -C₃)alkylSO₂, tosyl or phenyl SO₂. Compounds in which R² is other than H are nolonger tautomeric. The percent of 2-substituted pyrazolo[3,4-g]guinolineversus the percent of the 1-substituted derivative, in fact, gives anindication of the percent of each tautomer prior to reaction with thesulfonyl chloride. The amount of XVII in which R² is H compared with theamount in which R² is a sulfonyl group depends on the amount of sulfonylhalide employed. Obviously, two molar or greater amount of sulfonylhalide will produce a 2(or 1)-sulfonyl-7-sulfonyloxymethyl derivative,but quantities less than two moles produce a mixture of the 2(or1)-sulfonyl-7-sulfonyloxymethyl derivative and the 7-sulfonyloxymethyltautomeric mixture unsubstituted in the pyrazole ring. Reaction of XVIIwith sodium methylate, methylmercaptan sodium salt, sodium cyanide,sodium methanesulfinate or other basic salts of methanol,methylmercaptan etc. yields compounds according to Formula Ia, Ib, Ic orId in which X is SCH₃, OCH₃, CN or SO₂ CH₃. These basic reactionconditions also serve to hydrolyze the sulfonyl group in the pyrazolering, if any, to produce a tautomeric mixture XVIII (of which only the2-tautomer is illustrated). Compounds in which X is CONH₂ are preparedby hydration of the corresponding cyano compound.

This invention is further illustrated by the following specificexamples.

EXAMPLE 1 Preparation of trans-dl-4,4a,5,6,7,8,8a,9-1H and2H-pyrazolo[3,4-g]quinoline

A reaction mixture was prepared from 65 g. of 4-benzoyloxycyclohexanone,38 ml. of pyrrolidine, a few crystals of p-toluenesulfonic acidmonohydrate, and 1000 ml. of benzene. The reaction mixture was heated torefluxing temperature under a nitrogen atmosphere for one hour in anapparatus equipped with a Dean-Stark water trap. The reaction mixturewas then cooled and the volatile constituents removed by evaporation invacuo. The residue, comprising the pyrrolidine enamine of4-benzoyloxycyclohexanone formed in the above reaction, was dissolvedwithout further purification in 1000 ml. of dioxane. 64 g. of acrylamidewere added. This new reaction mixture was heated under a nitrogenatmosphere at reflux temperature for two days after which time it wascooled and the volatile constituents removed by evaporation in vacuo.The reaction mixture was diluted with ethyl acetate and the ethylacetate layer separated, washed first with water and then with saturatedaqueous sodium chloride. The ethyl acetate layer was dried and thevolatile constituents removed by evaporation in vacuo. The resultingresidue, comprising a mixture of2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and2-oxo-6-benzoyloxy- 3,4,4a,5,6,7,-hexahydroquinoline formed in the abovereaction, was dissolved in chloroform and the chloroform solutionchromatographed over florisil. Chloroform containing increasing amountsof ethanol (0 to 2 percent) was used as the eluant. Fractions found tocontain 2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and its Δ⁸(8a)isomer by thin-layer chromatography were combined and the solventremoved therefrom in vacuo. The resulting residue was crystallized bytriturating with hexane to yield a crystalline mixture of6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinolin-2-one and thecorresponding 3,4,4a,5,6,7-hexahydro derivative. The mixture melted inthe range 130°-150° C. after recrystallization from an ether-hexanesolvent mixture.

Analysis: Calculated: C, 70.83; H, 6.32; N, 5.16. Found: C, 71.05; H,6.19; N, 5.33.

NMR of the product isolated above indicated that the mixture containedabout 60 percent of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinolin-2-oneand 40% of the 3,4,4a,5,6,7-hexahydro isomer.

A mixture of 2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and itsΔ⁸(8a) isomer obtained from 65 g. of 4-benzoyloxycyclohexanone as abovewithout further purification was dissolved in a mixture of 300 ml. oftetrahydrofuran (THF) and 300 ml. of dimethylformamide. 14 g. of sodiumhydride were added, thus forming the sodium salt of the quinoline. Thismixture was stirred at ambient temperature for about 20 minutes under anitrogen atmosphere after which time 55 g. of benzyl bromide in 75 ml.of THF were slowly added over a 10 minute period. The reaction mixturewas stirred for an additional hour in the range 32°-45° C. and was thendiluted with water. The aqueous mixture was extracted with ethylacetate. The ethyl acetate extract was separated, washed with water andwith saturated aqueous sodium chloride, and then dried. Evaporation ofthe ethyl acetate yielded a mixture of1-benzyl-2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and1-benzyl-2-oxo-6-benzoyloxy-3,4,4a,5,6,7-hexahydroquinoline; yield=106g.

106 g. of the above mixture were dissolved in 1 l. of THF and thesolution cooled in an ice-water bath. 40 g. of lithium aluminumhydridewere added thereto in portions. After the addition had been completed,the reaction mixture was heated to refluxing temperature under anitrogen atmosphere for about 4 hours. The reaction mixture was thencooled and excess lithium aluminumhydride destroyed by the addition ofethyl acetate. 10 percent aqueous sodium hydroxide was added todecompose any organometallic compounds present in the mixture. At thispoint, the reaction mixture was diluted with water. The resultingaqueous mixture was extracted several times with chloroform. Thechloroform extracts were separated and combined. The combined extractswere washed with saturated aqueous sodium chloride and then dried.Evaporation of the chloroform yielded a residue comprising a mixture of1-benzyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and1-benzyl-6-hydroxy-1,2,3,4,4a,5,6,7-octahydroquinoline. (Both the 2-oxogroup and the 6-benzoyloxy group reacted with the lithium aluminumhydride to yield an octahydroquinoline with a free alcohol at C-6). Themixture of compounds thus obtained was dissolved in ether, the etherealsolution cooled, and gaseous anhydrous hydrogen chloride passed into thesolution, thus forming the hydrochloride salts of the quinoline isomers.The quinoline hydrochlorides were insoluble and were separated bydecantantation of the ether. The residual salts were dissolved in 100ml. of methanol and 400 ml. of THF. The solution was cooled and 30 g. ofsodium cyanoborohydride added thereto in portions. After the additionhad been completed, the cooling bath was removed and the reactionmixture stirred at ambient temperature for 1.25 hours, after which timeit was poured into a mixture of 1 N aqueous hydrochloric acid and ice.The acidic solution was extracted with ether, and the ether extractdiscarded. The acidic solution was then made basic with 10 percentaqueous sodium hydroxide and the alkaline mixture extracted severaltimes with a chloroform-isopropanol solvent mixture. The organicextracts were combined, and the combined extracts washed with saturatedaqueous sodium chloride and then dried. Evaporation of the solventyielded trans-dl-1-benzyl-6-hydroxydecahydroquinoline formed in theabove reaction; yield=53.6 g. Total yield in 6 steps was 73 percentbased upon recovered 4-benzoyloxycyclohexanone starting material.

53 g. of trans-dl-1-benzyl-6-hydroxydecahydroquinoline were dissolved in1.5 l. of methylene dichloride and the solution cooled in an ice-waterbath. 50 g. of cyanogen bromide were added and the resulting mixturestirred at room temperature for 15 hours. The reaction mixture waswashed successively with 1 N aqueous hydrochloric acid and water, andwas then dried. Evaporation of the solvent yielded a residue containingtrans-dl-1-cyano-6-hydroxydecahydroquinoline formed in the abovereaction. The residue was dissolved in chloroform and the chloroformsolution chromatographed over 300 g. of florisil using chloroformcontaining increasing amounts (0-2%) of methanol as the eluant.Fractions shown by TLC to contain the desired cyano compound werecombined and the solvent removed from the combined fraction byevaporation in vacuo. trans-dl-1-cyano-6-hydroxydecahydroquinoline thusprepared weighed 22.5 g.

22.5 g. of trans-dl-1-cyano-8-hydroxydecahydroquinoline were dissolvedin 1200 ml. of methylene dichloride. 33 g. of pyridinehydrochloride:chromium trioxide (Sarett's Reagent) were added. Thereaction mixture was stirred at room temperature under nitrogen forabout 6 hours, and was then filtered. The filtrate was concentrated invacuo and the concentrate chromatographed over 300 g. of florisil usingchloroform containing 1 percent methanol as the eluant. Fractions shownby TLC to contain trans-dl-1-cyano-6-oxodecahydroquinoline formed in theabove reaction were combined and the combined fractions evaporated todryness in vacuo. Recrystallization of the resulting residue from anether-chloroform solvent mixture yieldedtrans-dl-1-cyano-6-oxodecahydroquinoline melting at 86°-8° C.;yield=18.9 g.

Analysis: Calculated: C, 67.39; H, 7.92; N, 15.72. Found: C, 67.15; H,7.75; N, 15.46.

17.6 g. of trans-dl-1-cyano-6-oxodecahydroquinoline were dissolved in200 ml. of benzene to which 100 g. of the dimethylacetal ofdimethylformamide had been added. The reaction mixture was heated torefluxing temperature under nitrogen for about 20 hours and was thencooled. Evaporation of the solvent in vacuo yielded a residue comprisingtrans-dl-1-cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline formedin the above reaction. The compound was purified by chromatography over300 g. of florisil using chloroform containing increasing amounts (0-2%)of methanol as the eluant. 10.2 g. oftrans-dl-1-cyano-6-oxo-7-dimethylaminomethylenedecahydroquinolinemelting at 159°-163° C. were obtained. The compound was crystallizedfrom toluene to yield crystals melting at 162°-4° C.

Analysis: Calculated: C, 66.92; H, 8.21; N, 18.01. Found: C, 67.14; H,8.16; N, 18.04.

10.2 g. oftrans-dl-1-cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline weredissolved in 400 ml. of methanol. 2.8 g. of 85 percent hydrazine wereadded and the subsequent reaction mixture stirred for about 1 day undera nitrogen atmosphere. The volatile constituents were then removed byevaporation in vacuo. The residue was dissolved in chloroform and thechloroform solution chromatographed over 150 g. of florisil usingchloroform containing increasing amounts (2-5%) of methanol as theeluant. Fractions shown by TLC to contain the desiredoctahydropyrazoloquinoline were combined and the solvent evaporatedtherefrom to dryness; yield=6.3 g. Recrystallization of the residue fromethanol yielded a mixture oftrans-dl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its 1H tautomer melting at 193°-5° C.

Analysis: Calculated: C, 65.32; H, 6.98; N, 27.70 Found: C, 65.48; H,6.80; N, 27.64.

A reaction mixture prepared from 860 mg oftrans-dl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline, 5 g. of zinc dust, 10 ml. of water and 50ml. of acetic acid. The mixture was heated to refluxing temperatureunder a nitrogen atmosphere for 18.5 hours after which time it wasfiltered and the filtrate poured over ice. The resulting aqueous mixturewas then made basic with 14 N ammonium hydroxide and the resultingalkaline aqueous layer extracted several times with achloroform-isopropanol solvent mixture. The organic extracts werecombined and the combined extracts washed with saturated aqueous sodiumchloride and then dried. Evaporation of the solvent yielded a residuecomprisingtrans-dl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline and the1H tautomer formed in the above reaction. The residue was dissolved inethanol and 0.70 ml. of 12 N aqueous hydrochloric acid added thereto.The mixture oftrans-dl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline and the1H-tautomer dihydrochlorides formed as above melted at 284°-7° C.;yield=780 mg.

Analysis: Calculated: C, 48.01; H, 6.85; N, 16.80. Found: C, 48.07; H,7.05; N, 16.83.

EXAMPLE 2

Preparation of trans-dl-5-n-Propyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline

A reaction mixture was prepared from 6.3 g. of a mixture oftrans-dl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its 1H-tautomer (prepared by the procedure of the above example), 30g. of zinc dust, 375 ml. of acetic acid and 75 ml. of water. Thereaction mixture was heated to refluxing temperature under nitrogen for16 hours after which time it was filtered and the filtrate poured overice. The resulting aqueous mixture was made basic by the addition of 14N aqueous ammonium hydroxide and the alkaline layer extracted severaltimes with a chloroform-isopropanol solvent mixture. The organicextracts were combined, the combined extracts washed with saturatedaqueous sodium chloride and then dried. Evaporation of the solventyielded a residue comprisingtrans-dl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline and its1H-tautomer formed in the above reaction. The residue was dissolved in500 ml. of methanol to which was added 1.9 g. of sodiumcyanoborohydride. Next 20 ml. of propionaldehyde were added and theresulting mixture stirred at ambient temperature under a nitrogenatmosphere for 28 hours. The reaction mixture was then poured into 1 Naqueous hydrochloric acid. The aqueous layer was extracted with etherand the ether extracts discarded. The aqueous layer was then made basicby the addition of an excess of 14 N aqueous ammonium hydroxide and theresulting alkaline layer extracted several times with achloroform-isopropanol solvent mixture. The organic extracts werecombined and the combined extracts washed with saturated aqueous sodiumchloride and then dried. Evaporation of the solvent yielded a residuecomprising trans-dl-5-n-propyl-4,4a,5,6,7,8,8a, 9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline formed in the above reaction. Mass spectrum:M⁺ =219.

The residue was dissolved in 100 ml. of boiling acetone to which wereadded 5 ml. of 12 N aqueous hydrochloric acid in dropwise fashion. Themixture was cooled and the dihydrochlorides oftrans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline thus formed separated by filtration;yield=4.6 g.; m.p.=250°-7° C.

Analysis: Calculated: C, 53.43; H, 7.93; N, 14.38; Cl, 24.26. Found: C,53.15; H, 7.91; N, 14.47; Cl, 24.33.

Using the above procedure, 1.2 g. of a mixture oftrans-dl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its mixture of 1H-tautomer were reacted with zinc dust and aceticacid to form a mixture oftrans-dl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline and its1H tautomer which was isolated as a residue. This residue dissolved in50 ml. of DMF to which were added 1.7 g. of potassium carbonate. Next,0.6 ml. of n-propyl iodide were added and the resulting mixture stirredat ambient temperature for about 4 hours under a nitrogen atmosphere.The reaction mixture was diluted with water and the resulting aqueousmixture extracted several times with ethyl acetate. The ethyl acetateextracts were combined and the combined extracts washed successivelywith water and saturated aqueous sodium chloride and were then dried.Evaporation of the ethyl acetate yielded a residue comprisingtrans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its 1H tautomer which was purified by chromatography over 30 g. offlorisil using chloroform containing increasing amounts (2-10%) ofmethanol as the eluant. Fractions shown by TLC to containtrans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H and1H-pyrazolo[3,4-g]quinoline were combined and the combined extractsevaporated to dryness to yield 0.28 g. oftrans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its 1H tautomers. The residue was dissolved in ethanol to which wasadded 0.16 ml. of 12 N aqueous hydrochloric acid, thus forming thedihydrochlorides oftrans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand the 1H tautomer. The reaction mixture was concentrated in vacuo andthe concentrate diluted with ether. A mixture oftrans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline dihydrochloride crystallized and wasseparated by filtration; m.p.=276°-8° C.

EXAMPLE 3 Preparation oftrans-dl-5-n-Propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline

A mixture of 10 ml. of n-propyl amine and 400 ml. of toluene were cooledin an ice-water bath. A solution of 16.5 g. of ethylα-(bromomethyl)-acrylate in 50 ml. of toluene was added thereto indropwise fashion. The resulting mixture was stirred with cooling forabout 25 minutes. Next, a solution of 11 g. of 4-benzoyloxycyclohexanonein 75 ml. of toluene was added in dropwise fashion. This new mixture washeated under a nitrogen atmosphere to refluxing temperature for about 23hours. The reflux condenser was equipped with a Soxhlet extractorcontaining a 5 A sieve to remove water. Next the reaction mixture wascooled and the cooled mixture filtered. Evaporation of the filtrateyielded a residue comprising a mixture of1-n-propyl-3-ethoxycarbonyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydroquinolineand1-n-propyl-3-ethoxycarbonyl-6-benzoyloxy-1,2,3,4,4a,5,6,7-octahydroquinoline.The residue was dissolved in an ether-chloroform solvent mixture and theresulting solution saturated with gaseous hydrogen chloride whilemaintaining the temperature in the range 0°-5° C. The solvent wasdecanted from the crystalline hydrochloride salts thus formed. The saltswere dissolved in 100 ml. of methanol. 300 ml. of THF were added and theresulting solution cooled in an ice-water bath. 15 g. of sodiumcyanoborohydride were added in portions to the stirred and cooledreaction mixture. After the addition had been completed, the reactionmixture was stirred for another 1.25 hours after which time it wasdiluted with aqueous sodium bicarbonate. The aqueous alkaline mixturewas extracted several times with ethyl acetate. The ethyl acetateextracts were combined and the combined extracts washed with saturatedaqueous sodium chloride solution and then dried. Evaporation of thesolvent yieldedtrans-dl-1-n-propyl-3-ethoxycarbonyl-6-benzoyloxydecahydroquinoline. Thecompound was dissolved in a mixture of 400 ml. of methanol and 100 ml.of 2 N aqueous sodium hydroxide. This mixture was stirred at ambienttemperature under a nitrogen atmosphere for 64 hours after which timethe volatile constituents were removed by evaporation in vacuo. Theresulting residue was suspended in 800 ml. of ethanol and 15 ml. of 12 Naqueous hydrochloric acid. The esterification mixture was heated torefluxing temperature and about 300 ml. of solvent removed bydistillation. 300 ml. of additional ethanol were added and the reactionmixture heated to refluxing temperature for 26 hours in an apparatusequipped with a Soxhlet trap containing a 3 A sieve. The reactionmixture was cooled, diluted with aqueous sodium bicarbonate and thealkaline mixture extracted several times with chloroform. The chloroformextracts were combined and the combined extracts washed with saturatedaqueous sodium chloride and then dried. Evaporation of the chloroformyielded 10.3 g. of a residue comprisingtrans-dl-1-n-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline formedin the above hydrolysis after chromatography over 150 g. of florisilusing chloroform containing increasing amounts (2-10%) of methanol asthe eluant.

A solution was prepared from 8.8 g. oftrans-dl-1-n-propyl-3-ethoxycarbonyl-6-hydroxydecahydroquinoline and 400ml. of methylene dichloride. 4.1 g. of sodium acetate were added. Next,10.8 g. of pyridine hydrochloride:chromium trioxide were added and theresulting mixture stirred for about 22 hours. The reaction mixture wasfiltered and the filtrate concentrated in vacuo. The resultingconcentrate was dissolved in chloroform and the chloroform solutionchromatographed over 150 g. of florisil using chloroform containingincreasing amounts (1-2%) of methanol as the eluant. Fractions shown bythin-layer chromatography to containtrans-dl-1-n-propyl-3-ethoxycarbonyl-6-oxodecahydroquinoline formed inthe above reaction were combined and the solvent removed from thecombined extracts to yield 3.48 g. of the 6-oxo compound as a residue.The 6-oxo compound was dissolved in 100 ml. of toluene containing anadded 25 ml. of the dimethylacetal of dimethylformamide. The resultingmixture was heated to refluxing temperature under a nitrogen atmospherefor 44 hours and was then allowed to remain at room temperature for anadditional 4 days. Volatile constituents were removed by evaporation invacuo and the residue, comprisingtrans-dl-1-n-propyl-3-ethoxycarbonyl-6-oxo-7-(dimethylaminomethylene)decahydroquinolineformed in the above reaction, was purified by chromatographing achloroform solution of the compound over florisil using chloroformcontaining increasing amounts (2-5%) of methanol as the eluant.Fractions shown by TLC to contain the desired 7-dimethylaminomethylenecompound were combined and the solvent evaporated therefrom in vacuo.

A solution was prepared from 2.24 g. oftrans-dl-1-n-propyl-3-ethoxycarbonyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline and 150 ml. of ethanol. 0.45 ml. of hydrazine hydratewere added and the resulting mixture stirred at ambient temperature forabout 17 hours. The reaction mixture was evaporated to dryness in vacuo.The residue containing a mixture oftrans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineandtrans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolinewas dissolved in chloroform and the resulting solution chromatographedover 35 g. of florisil using chloroform containing 2 percent methanol asan eluant. Fractions shown to contain the desired pyrazoloquinoline byTLC were combined and the solvent evaporated therefrom in vacuo.Recrystallization from a mixture of ether and hexane yieldedtrans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its 1H tautomer melting at 125°-7° C.

Analysis: Calculated: C, 65.95; H, 8.65; N, 14.42. Found: C, 65.75; H,8.42; N, 14.16.

EXAMPLE 4 Preparation oftrans-dl-5-n-Propyl-7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline

A mixture oftrans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinedihydrochloride and the dihydrochloride salt of the 1H tautomer (3.7millimoles) was suspended in 200 ml. of THF. 1 g. of lithiumaluminumhydride was added thereto in portions. The consequent reactionmixture was stirred at ambient temperature under a nitrogen atmospherefor about 16 hours, and was then cooled. Ethyl acetate and 10 percentaqueous sodium hydroxide were added thereto seriatium to react with anyexcess lithium aluminumhydride and to decompose organometallic compoundspresent. The reaction mixture so treated was then diluted with water andthe aqueous mixture extracted several times with a chloroformisopropanolsolvent mixture. The organic layers were separated and combined. Thecombined layers were washed with saturated aqueous sodium chloride andthen dried. Evaporation of the solvent yielded a mixture oftrans-dl-5-n-propyl-7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its 1H tautomer. The residue was dissolved in ethanol to which wasadded 0.2 ml. of 12 N aqueous hydrochloric acid. Evaporation of thevolatile constituents yielded a residue comprisingtrans-dl-5-n-propyl-7-hydroxymethyl-4,4a,5,6,7,8,8a, 9-octahydro-2H and1H-pyrazolo[3,4-g]quinoline dihydrochlorides. The residue was dissolvedin a mixture of methanol and acetone to yield crystals melting at270°-5° C. with decomposition; yield=350 mg.

The above reaction was repeated with 1.55 g. oftrans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinein THF being reduced with an excess of lithium aluminumhydride. Theproduct of the reaction,trans-dl-5-n-propyl-7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline, was crystallized from a mixture ofchloroform and ethanol to yield crystalline material melting at 167°-9°C.

Analysis: Calculated: C, 67.43; H, 9.30; N, 16.85; Found: C, 67.21; H,9.13; N, 16.62.

EXAMPLE 5 Preparation oftrans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline

A suspension was prepared from 1 millimole oftrans-dl-5-n-propyl-7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline in 100 ml. of pyridine. 1 ml. ofmethanesulfonyl chloride (mesyl chloride) was added and the resultingmixture left over night at ambient temperature. The mixture was dilutedwith dilute aqueous ammonium hydroxide and the resulting alkaline layerextracted several times with chloroform. The chloroform extracts werecombined and the combined extracts washed with saturated aqueous sodiumchloride and then dried. Evaporation of the solvent yielded a solidresidue. A chloroform solution of the residue was chromatographed over30 g. of florisil using chloroform containing increasing amounts (1-2%)of methanol as the eluant. Fractions shown by TLC to containtrans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinewere combined and the solvent was removed therefrom by evaporation.trans-dl-2-Methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinemelted 152°-4° C. after recrystallization from ether.

Analysis: Calculated: C, 47.39; H, 6.71; N, 10.36; S, 15.81. Found: C,47.60; H, 6.71; N, 10.32; S, 15.69.

A second fraction was obtained from the chromatography was shown by NMRto be a 2:1 mixture oftrans-dl-5-n-propyl-7-mesyloxymethyl-2-methanesulfonyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolineand its 1-methanesulfonyl-1H isomer.

EXAMPLE 6 Preparation oftrans-dl-5-n-Propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-1Hand 2H-pyrazolo[3,4-g]quinoline

1 g. of methylmercaptan was dissolved in 40 ml. of dimethylformamide.The solution was cooled in an ice-water bath. About 1 g. of sodiumhydride (as a 50% suspension in mineral oil) was added thereto inportions. The cooling bath was removed and a solution containing 0.4 g.oftrans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolinecontaining sometrans-dl-1-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[5,4-g]quinolinein 10 ml. of DMF prepared as in Example 5 was added. The reactionmixture was stirred at ambient temperature for about 5 hours and wasthen diluted with water. The aqueous mixture was extracted several timeswith ethyl acetate. The ethyl acetate extracts were separated andcombined. The combined extracts were washed with water and withsaturated aqueous sodium chloride and then dried. Evaporation of thesolvent yielded an oily residue comprisingtrans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-1Hand 2H-pyrazolo[3,4-g]quinoline; yield=0.17 g. The residue was dissolvedin ethanol and attempts made to prepare both the hydrochloride and theoxalate salts. Both salts initially turned out to be noncrystalline. Thefree bases were then recovered from the noncrystalline oxalate bydissolving the oxalate in water, adding base and extracting the mixturewith ether.trans-dl-5-n-Propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-1Hand 2H-pyrazolo[3,4-g]quinoline thus purified crystallized onevaporation of the ether; melting point=175°-7° C.; yield=40 mg.

Analysis: Calculated: C, 64.47; H, 9.02; N, 15.04; S, 11.47. Found: C,64.47; H, 8.96; N, 15.09; S, 11.29.

The above purified free base tautomeric mixture was dissolved in ethanoland an excess of 12 N hydrochloric acid added. The volatile constituentswere removed by evaporation and the resulting residue comprising thecorresponding dihydrochloride salts crystallized from anacetone-methanol solvent mixture.

Analysis: Calculated: C, 51.13; H, 7.72; N, 11.93; Cl, 20.10; S, 9.10;Found: C, 50.89; H, 7.57; N, 12.15; Cl, 20.18; S, 9.31.

EXAMPLE 7 Preparation oftrans-dl-5-Methyl-4,4a,5,6,7,8,8a,9-octahydro-1H and2H-pyrazolo[3,4-g]quinoline

46.5 g. of the isomer mixture containing about 60 percent of6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinoline-2-one and 40% of the3,4,4a,5,6,7-hexahydro isomer were dissolved in 400 ml. oftetrahydrofuran (THF). 80 ml. of methyl iodide were added and theresulting mixture cooled in an ice-water bath. 9.6 g. of sodium hydride(as a 50 percent suspension in mineral oil) were added in portions.After all of the sodium hydride suspension had been added, the coolingbath was removed and the reaction mixture stirred at ambient temperatureunder a nitrogen atmosphere for about 4 hours. The reaction mixture wasthen diluted with water and the aqueous mixture thoroughly extractedwith chloroform. The chloroform extracts were combined and the combinedextracts washed with saturated aqueous sodium chloride and then dried.The chloroform was removed by evaporation to dryness in vacuo leaving asa residue an orange oil weighing 47.3 g. Crystallization of the residuefrom an ether-hexane solvent mixture yielded crystals of1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and thecorresponding 3,4,4a,5,6,7-hexahydro isomer.

Analysis: Calculated: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.33; H,6.90; N, 4.67.

A solution of 47.3 g. of a mixture of1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and thecorresponding 3,4,4a,5,6,7-hexahydro isomer as obtained above weredissolved in 800 ml. of THF and the solution cooled to about 0° C. 20 g.of lithium aluminumhydride were added thereto in portions and theresulting mixture refluxed for four hours under a nitrogen atmosphere.The reaction mixture was cooled and excess lithium aluminumhydridedestroyed by the addition of ethyl acetate. 10% sodium hydroxide wasthen added and the mixture diluted with water to decompose anyorganometallics present. The aqueous mixture was extracted several timeswith a chloroform-isopropanol solvent mixture. The organic extracts werecombined and the combined extracts washed with saturated aqueous sodiumchloride and then dried. Evaporation of the solvent yielded as a residuea mixture of theenamines--1-methyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and1-methyl-6-hydroxy-1,2,3,4,4a,5,6,7-octahydroquinoline--formed in theabove reaction. (The lithium aluminumhydride reduction served to removethe benzoyl group at C-6 as a benzyl alcohol moiety, leaving a freehydroxyl in that position). The above residue, without furtherpurification, was dissolved in about 300 ml. of ether and the etherealsolution saturated with gaseous hydrogen chloride, thus forming thehydrochloride salt of the enamine mixture. The ether was removed bydecantation and the residue dissolved in a mixture of 200 ml. of THF and50 ml. of methanol. The solution was cooled in an ice-water bath. 12 g.of sodium cyanoborohydride were added with cooling and stirring. Afterall of the cyanoborohydride had been added, the reaction mixture wasstirred for another 60 minutes and then poured over a mixture of ice and1 N aqueous hydrochloric acid. The acidic aqueous solution was extractedwith chloroform and the chloroform extract discarded. The solution wasthen made basic with 14 N aqueous ammonium hydroxide.Trans-dl-1-methyl-6-hydroxydecahydroquinoline formed in the abovereaction, being insoluble in the alkaline medium, separated and wasextracted several times with a chloroform-isopropanol solvent mixture.The combined extracts were washed with saturated aqueous sodium chlorideand then dried. Evaporation of the solvent yielded 15 g. oftrans-dl-1-methyl-6-hydroxydecahydroquinoline.

Fifteen grams of trans-dl-1-methyl-6-hydroxydecahydroquinoline weredissolved in 250 ml. of 6 N aqueous sulfuric acid. The solution wascooled in an ice-water bath. A solution of 9 g. of chromium trioxide in60 ml. of 6 N aqueous sulfuric acid were added thereto with stirring indropwise fashion over a 10-minute period. The cooling bath was removedand the reaction mixture stirred for an additional 60 minutes at ambienttemperature. The excess oxidizing agent was decomposed by addingisopropanol to the reaction mixture. The reaction mixture was nextpoured over ice and the acidic aqueous solution made basic with 14 Naqueous ammonium hydroxide. trans-dl-1-Methyl-6-oxodecahydroquinolinethus formed, being insoluble in the alkaline layer, separated and wasextracted several times with a mixture of chloroform and isopropanol.The extracts were combined and the combined extracts washed withsaturated aqueous sodium chloride and then dried. Evaporation of thesolvent in vacuo yielded trans-dl-1-methyl-6-oxodecahydroquinolineboiling in the range 105°-116° C. at 6 torr; yield=7.7 g. (45%).

A reaction mixture was prepared from 7.7 g. oftrans-dl-1-methyl-6-oxodecahydroquinoline, 36 g. of the dimethyl acetalof dimethylformamide and 250 ml. of benzene. Benzene was removed bydistillation at atmospheric pressure under nitrogen until about 1/2 theoriginal volume remained (1.25 hours). Sufficient benzene was then addedto make up the volume to the original volume and the process wasrepeated (four times). All of the benzene was finally removed byevaporation in vacuo and the resulting residue dissolved in 100 g. ofdimethylformamide dimethylacetal. This solution was heated to refluxingtemperature under nitrogen for 20 hours. The reaction mixture was thenevaporated in vacuo and a chloroform solution of the residuechromatographed over 150 g. of florisil using as the eluant, methylenedichloride containing increasing amounts (1-5%) of methanol. Fractionscontaining similar substances as shown by TLC were combined. The thirdsubstance to be eluted was a yellow solid (wt=3 g.) The solid was heatedwith 100 ml. of ether and the resulting solution filtered. Concentrationof the filtrate to about 50 ml. yielded 590 mg. of crystals oftrans-dl-1-methyl-6-oxo-7-dimethylaminomethylenedecahydroquinolinemelting at 107°-109° C.

Analysis: Calculated: C, 70.23; H, 9.97; N, 12.60. Found: C, 70.17; H,9.74; N, 12.87.

A solution was prepared by dissolving 175 mg. oftrans-dl-1-methyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline in 10ml. of methanol. 0.05 ml. of hydrazine hydrate were added and theresulting reaction mixture stirred at room temperature under a nitrogenatmosphere for 4.5 days. The volatile constituents were removed byevaporation. A chloroform solution of the residue was chromatographedover 25 g. of florisil using chloroform containing increasing amounts(2-15%) of methanol as the eluant. Fractions shown by TLC to contain asubstance moving close to the origin and different than startingmaterial were combined and the solvent removed from the combinedfractions by evaporation.trans-dl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-(and2H)-pyrazolo[3,4-g]quinoline free base gave a molecular ion (M⁺) at 191by mass spectroscopy.

The resulting residue was dissolved in ethanol and 2 ml. of 1 Nhydrochloric acid were added. The acidic solution was evaporated todryness. Crystallization of the residue from ethanol yielded atautomeric mixture containingtrans-dl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-(and2H)-pyrazolo[3,4-g]quinoline dihydrochlorides melting at 268°-70° C.with decomposition; yield=140 mg.

Analysis: Calculated: C, 50.01; H, 7.25; N, 15.90; Cl, 26.84. Found: C,49.82; H, 7.08; N, 15.66; Cl, 26.80.

EXAMPLE 8 Alternate Preparation of1-n-Propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and1-n-Propyl-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone

A reaction mixture was prepared containing 4.4 g. of4-benzoyloxycyclohexanone [prepared by the procedure of E. R. H. Jonesand F. Sondheimer, J. Chem. Soc., 615 (1949)], 2.5 ml. of n-propylamineand 100 ml. toluene. The mixture was heated to reflux temperature forabout 2 hours under a nitrogen atmosphere using a Dean-Stark water trap.The reaction mixture was then heated to refluxing temperature for anadditional 2 hours in the presence of a molecular sieve to remove water.The reaction mixture was cooled and the solvent removed by evaporationin vacuo. 4 ml. of methyl acrylate and 100 ml. of dioxane were added tothe residue and the resulting mixture was refluxed overnight under anitrogen atmosphere. The reaction mixture was again cooled and thevolatile constituents removed by evaporation in vacuo. Chromatography ofan ethereal solution of the resulting residue over 200 g. of florisilusing ether as an eluant yielded a mixture of1-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and1-n-propyl-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone:yield=2.15 g.

EXAMPLE 9 Preparation oftrans-dl-5-allyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and2H)-pyrazolo[3,4-g]quinoline

Following the procedure of Example 1, 65 g. of4-benzoyloxycyclohexanone, 38 ml. of pyrrolidine and a few crystals ofp-toluenesulfonic acid monohydrate were dissolved in 1000 ml. ofcyclohexane. The resulting mixture was heated to reflux in a nitrogenatmosphere using a Dean-Stark water trap for about 1/2 hour. The mixturewas then cooled and the solvents removed by evaporation in vacuo. Theresidue, comprising the pyrrolidine enamine of4-benzoyloxycyclohexanone, was mixed with 53 g. of acrylamide in 1000ml. of dioxane. The reaction mixture was heated to reflux temperature ina nitrogen atmosphere for about one day after which time it was cooledand the volatile constituents removed by evaporation. The resultingresidue was diluted with water and the aqueous mixture extracted withethyl acetate. The ethyl acetate extract was separated, washed withwater and with saturated aqueous sodium chloride and then dried.Evaporation of the solvent yielded a mixture of6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinoline-2-one and thecorresponding 3,4,4a,5,6,7-hexahydro compound.

The above mixture was dissolved in a combination of 250 ml. oftetrahydrofuran and 250 ml. of dimethylformamide. 12 g. of sodiumhydride as a 50% suspension in mineral oil was added and the mixturestirred in order to completely form the sodium salt of thequinoline-2-one. Next 30 g. of allyl bromide as a solution in 75 ml. ofTHF were added and the resulting mixture stirred for 24 hours. Thetemperature of the reaction mixture rose rapidly and external coolingwas supplied. After the reaction had been completed, the reactionmixture was diluted with water and the aqueous mixture extracted withethyl acetate. The ethyl acetate extract was separated, washed withwater and with saturated aqueous sodium chloride and then dried.Evaporation of the solvent yielded a mixture of1-allyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-1H-quinoline-2-one and thecorresponding 3,4,4a,5,6,7-hexahydro compound.

The N-allyl derivative thus prepared was dissolved in 750 ml. of THF andthe solution cooled in an ice-water bath. 20 g. of lithium aluminumhydride were added thereto in portions. After the addition had beencompleted, the resulting mixture was heated to reflux temperature undera nitrogen atmosphere for about three hours. The reaction mixture wasthen cooled in an ice-water bath and the excess lithium aluminum hydridedecomposed by the addition of ethyl acetate. 10% aqueous sodiumhydroxide was added to decompose any organometallic compounds presentand the mixture thus treated was diluted with water. The aqueous mixturewas then extracted several times with chloroform and the chloroformextracts combined. The combined extracts were washed with saturatedaqueous sodium chloride and dried. Evaporation of the solvent yielded aresidue comprising a mixture of1-allyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and its1,2,3,4,4a,5,6,7-octahydro isomer. The residue was dissolved in 750 ml.of ether and the ethereal solution saturated with anhydrous gaseoushydrogen chloride. The hydrochloride salt of the octahydroquinolinemixture, being insoluble in ether, precipitated and the ether wasseparated by decantation. The hydrochloride was dissolved in a mixtureof 100 ml. of methanol and 300 ml. of THF. This solution was cooled inan ice-water bath. 20 g. of sodium cyanoborohydride were added theretoin portions while the reaction mixture was being cooled. After theaddition had been completed, the cooling bath was removed. The reactionwas stirred at ambient temperature for about 1 hour, and was thendiluted with saturated aqueous sodium bicarbonate. The alkaline layerwas extracted several times with chloroform. The chloroform extractswere combined and the combined extracts washed with saturated aqueoussodium chloride and then dried. Evaporation of the solvent yielded about12.8 g. of trans-dl-1-allyl-6-hydroxydecahydroquinoline.

The trans-dl-1-allyl-6-hydroxy-decahydroquinoline thus prepared wasdissolved in 500 ml. of methylenedichloride to which had been added 8.2g. of sodium acetate. Next 21.6 g. of pyridine hydrochloride/chromiumtrioxide were added. The reaction was stirred for 7.5 hours under anitrogen atmosphere at ambient temperature, and was then filtered. Thefiltrate was concentrated in vacuo. Chromatography of the filtrate over150 g. of florisil using chloroform containing increasing amounts (1-5%)methanol as the eluant yielded 3.2 g. oftrans-dl-1-allyl-6-oxodecahydroquinoline formed in the above reaction.The 6-oxo compound was dissolved in toluene and 25 ml. ofdimethylformamide dimethylacetal were added. The reaction mixture washeated to reflux temperature under a nitrogen atmosphere for 24 hoursafter which time it was cooled and the solvent removed by evaporation.The resulting residue was chromatographed over 150 g. of florisil usingchloroform containing increasing amounts (2-20%) of methanol as theeluant. Fractions shown by TLC to contain the desiredtrans-dl-1-allyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline formedin the above reaction were combined to yield after evaporation of thesolvent 1.3 g. of the desired product. This material was dissolved in 75ml. of methanol to which was added 0.5 ml. of hydrazine hydrate. Thereaction mixture was stirred at room temperature for about 20 hoursafter which time the volatile constituents were removed by evaporationin vacuo. A chloroform solution of the residue was chromatographed over35 g. of florisil using chloroform containing increasing amounts (2-4%)of methanol as the eluant. Fractions shown by TLC to contain the desiredtrans-dl-5-allyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline and its 1H tautomer were combined and thesolvent removed therefrom by evaporation in vacuo. Mass spectroscopy ofthe residue gave a molecular ion at 217. The residue, weighing 0.55 g.,was dissolved in 75 ml. of acetone and the acetone solution heated toreflux. 0.5 ml. of 12 N aqueous hydrochloric acid were added thereto indropwise fashion. The reaction mixture was allowed to cool.Trans-dl-5-allyl-4,4a,5,6,7,8,8a,9-octahydro-2H(and1H)-pyrazolo[3,4-g]quinoline dihydrochloride thus prepared melted atabout 215° C. with decomposition; weight=495 mg.

Analysis calculated: C, 53.80; H, 7.29; N, 1.48; Cl, 24.43 Found: C,53.52; H, 7.13; N, 1.65; Cl, 24.17.

As evidence of the utility of the compounds of this invention, it hasbeen found that they affect turning behavior in6-hydroxydopamine-lesioned rats in a test procedure designed to uncovercompounds useful for the treatment of Parkinsonism. In this test,nigroneostriatal-lesioned rats are employed, as prepared by theprocedure of Ungerstedt and Arbuthnott, Brain Res, 24, 485 (1970). Acompound having dopamine agonist activity causes the rats to turn incircles contralateral to the side of the lesion. After a latency period,which varies from compound to compound, the number of turns is countedover a 15-minute period.

Results obtained from testing representative compounds of this inventionin the rat turning test are set forth in Table 1 below. The compoundswere dissolved in water and the aqueous solution injected into the ratby the intraperitoneal route at dose levels of 1 mg/kg. and 100 mcg/kg.In the table, column 1 gives the name of the compound, column 2, percentof test animals exhibiting turning behavior, and column 3, averagenumber of turns observed in first 15 minutes after end of latencyperiod.

                                      TABLE 1                                     __________________________________________________________________________                    % of Rats                                                                     Exhibiting  Average                                                           Turning     Number of                                                         Behavior    Turns/rat                                         Name of Compound                                                                              1 mg./kg.                                                                          100 mcg./kg.                                                                         1 mg./kg.                                                                          100 mcg./kg.                                 __________________________________________________________________________    trans-dl-5-n-Propyl-4,4a,-                                                    5,6,7,8,8a,9-octahydro-1H                                                     and 2H-pyrazolo[3,4-g]quinoline                                               dihydrochloride 100  75     80   66                                           trans-dl-5-n-Propyl-7-                                                        methylmercaptomethyl-                                                         4,4a,5,6,7,8,8a,9-octahydro-                                                  1H and 2H-pyrazolo[3,4-g]-                                                    quinoline dihydrochloride                                                                     100  50     81   67                                           trans-dl-5-allyl-4,4a,5,6,-                                                   7,8,8a,9-octahydro-1H and 2H-                                                 pyrazolo[3,4-g]quinoline di-                                                  hydrochloride   100   0     165   0                                           __________________________________________________________________________

The compounds of this invention are also useful as prolactin inhibitorsand as such they can be employed in the treatment of inappropriatelactation such as postpartum lactation and galactorrhea. As evidence oftheir utility in the treatment of conditions in which it is desirable toreduce the prolactin level, the compounds of this invention have beenshown to inhibit prolactin according to the following procedure.

Adult male rats of the Sprague-Dawley strain weighing about 200 g. werehoused in an air-conditioned room with controlled lighting (lights on 6a.m.-8 p.m.) and fed lab chow and water ad libitum. Each rat received anintraperitoneal injection of 2.0 mg. of reserpine in aqueous suspension18 hours before administration of the test drug. The purpose of thereserpine was to keep prolactin levels uniformly elevated. The compoundsunder test were dissolved in 10 percent ethanol, and were injectedintraperitoneally at doses of 50 mcg/kg and 0.5 and 5 mg/kg. Eachcompound was administered at each dose level to a group of 10 rats, anda control group of 10 intact males received an equivalent amount of 10percent ethanol. One hour after treatment, all rats were killed bydecapitation, and 150 μl aliquots of serum were assayed for prolactin.

The difference between the prolactin level of the treated rats andprolactin level of the control rats, divided by the prolactin level ofthe control rats gives the percent inhibition of prolactin secretionattributable to the compounds of this invention. These inhibitionpercentages are given in Table 2 below. In the table, column 1 gives thename of the compound; and columns 2, 3 and 4, the percent prolactininhibition at 50 mcg./kg, and 0.5 and 5 mg./kg. dose levels.

                  TABLE 2                                                         ______________________________________                                                         Percent Prolactin                                                             Inhibition at Given Dose                                                        50 mcg/  0.5 mg/  5 mg/                                    Name of Compound   kg       kg       kg                                       ______________________________________                                        trans-dl-5-n-Propyl-4,4a,5-                                                   6,7,8,8a,9-octahydro-1H (and 2H)-                                             pyrazolo[3,4-g]quinoline                                                      dihydrochloride    61       -        91                                       trans-dl-5-methyl-4,4a,5,6,-                                                  7,8,8a,9-octahydro-1H (and 2H)-                                               pyrazolo[3,4-g]quinoline                                                      dihydrochloride    --       42       84                                       trans-dl-5-n-Propyl-7-methyl-                                                 mercaptomethyl-4,4a,5,6,7,8,8a,9-                                             octahydro-1h (and 2H)-pyrazolo-                                               [3,4-quinoline     --       48       73                                       ______________________________________                                    

In using the compounds of this invention to inhibit prolactin secretionor to treat Parkinson's syndrome or for other pharmacologic action, acompound according to Formula Ia or Ib above in which R is C₁ -C₃ alkylor allyl and R¹ is H or CH₂ X where X is OCH₃, SCH₃, SO₂ CH₃, CN orCONH₂, or a salt thereof with a pharmaceutically-acceptable acid, isadministered to a subject suffering from Parkinsonism or in need ofhaving his or her prolactin level reduced in an amount effective totreat Parkinsonism or to reduce prolactin. Oral administration ispreferred. If parenteral administration is used, the injection ispreferably by the subcutaneous route using an appropriate pharmaceuticalformulation. Other modes of parenteral administration such asintraperitoneal, intramuscular, or intravenous routes are equallyeffective. In particular, with intravenous or intramuscularadministration, a water soluble pharmaceutically-acceptable salt isemployed. For oral administration, the compounds either as the free baseor in the form of a salt thereof, can also be mixed with standardpharmaceutical excipients and loaded into empty telescoping gelatincapsules or pressed into tablets. The oral dosage range is from about0.01 to 10 mg./kg. of mammalian weight and the parenteral dose rangefrom about 0.0025 to 2.5 mg./kg. Intraperitoneal dosages of 10-100mg./kg. of trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and2H)-pyrazolo[3,4-g]quinoline dihydrochloride resulted in no deaths, butdosages of 300 mg./kg. were fatal, indicating an LD₅₀ in the range100-300 mg./kg.

We claim:
 1. A compound of the formula ##STR8## wherein R is (C₁-C₃)alkyl, allyl or benzyl and;R¹ is COOZ' wherein Z' is (C₁ -C₂)alkylor phenyl-substituted (C₁ -C₂)alkyl.
 2. A compound of the formula##STR9## wherein R is (C₁ -C₃)alkyl, allyl or benzyl and;R¹ is COOZ'wherein Z' is (C₁ -C₂)alkyl or phenyl-substituted (C₁ -C₂)alkyl.
 3. Acompound of the formula ##STR10## wherein R is (C₁ -C₃)alkyl, allyl orbenzyl and;R¹ is H or COOZ' wherein Z' is (C₁ -C₂)alkyl orphenyl-substituted (C₁ -C₂)alkyl.